Primary liver cancer is the most common malignant tumor in human with high mortality. However, the exact molecular mechanism of liver carcinogenesis is not completely defined and little is known about its prevention. On the basis of published data from our laboratory and exciting new preliminary findings, we hypothesize that cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX-2), the two most important rate-limiting key enzymes in the control of prostaglandin synthesis, importantly contribute to liver carcinogenesis through EP1 receptor-mediated activation of Akt. Therefore, interruption of the prostaglandin-associated signaling pathways may provide promising potential therapeutic targets for the chemoprevention and treatment of human liver cancer. This application proposes three specific aims to evaluate the above hypotheses. Aim I will examine the hypothesis that the cPLA2 and COX-2-mediated prostaglandin signaling pathways promote liver cancer development by utilizing animal models of hepatocarcinogenesis. Mice with disruption or targeted overexpression of cPLA2 and COX-2 in liver will be utilized to examine the spontaneous or hepatic carcinogen-induced liver cancer development. Aim II will evaluate the effect of overexpression or antisense/siRNA depletion of cPLA2 and COX-2 on liver cancer growth, in vitro and in SCID mice. Aim III is proposed to evaluate the hypothesis that activation of Akt by EP1 receptor is a key signaling pathway that mediates the cPLA2 and COX-2- induced liver cancer growth. The proposed studies will help understand the pathobiological functions and molecular mechanisms of cPLA2 and COX-2-controlled prostaglandin metabolism in liver cancer promotion and progression. The results will provide important therapeutic implications for the chemoprevention and treatment of human liver cancer. [unreadable] [unreadable]